Heart failure and its attendant morbidity and mortality are a significant and growing problem in the US. Little is known about the fundamental events that dictate the progression from the stable hypertrophied heart to decompensated ventricular dysfunction leading to the syndrome of heart failure. Evidence is emerging that derangements in cardiac fuel utilization and bioenergetics contribute to the pathologic remodeling of the hypertrophied heart. The peroxisome proliferator-activated receptors (PPARs) are a family of fatty acid-activated nuclear receptor transcription factors that control the expression of genes involved in myocardial energy metabolism. Recent evidence, generated by our group and others, indicates that PPARoc and its coactivator, PGC-1a, become deactivated in the pathologically hypertrophied heart. Conversely, the activity of this pathway is increased in physiologic forms of adaptive hypertrophy. We hypothesize that in the pathologically hypertrophied heart, deactivation of certain components of the gene regulatory cascade downstream of the inducible coactivator PGC-1a, leads to altered energetics and progressive ventricular dysfunction. This renewal proposal will use gain-of-function and loss-of-function strategies in mice and cultured cardiac myocytes to build upon our recent progress in delineating the regulatory pathways upstream and downstream of the PGC-1a gene regulatory cascade, to define the biologic function of this pathway, and to determine whether deactivation of specific components within this transcriptional regulatory circuitry contribute to the pathologic process that leads to irreversible ventricular dysfunction and heart failure in the context of chronic pressure overload. Experiments proposed in Specific Aim 1 are designed to characterize the cardiac phenotype of PGC-1a-deficient mice in response to chronic pressure overload or exercise training-induced cardiac hypertrophy. The goal of Specific Aim 2 is to delineate the biological function of PGC-lp in heart with comparison to PGC-1a. Specific Aim 3 is designed to investigate the basis for the pathologic cardiac remodeling response of mice deficient for the nuclear receptor, ERRa, a newly identified target of PGC-1a. Specific Aim 4 involves a series of intervention experiments aimed at modulating the PGC-1 regulatory cascade to rescue pathologic cardiac remodeling in the genetically engineered mouse models and in heart failure models using wild-type mice. A long-term goal is to identify new targets for the development of metabolic modulation therapy aimed at the prevention or amelioration of common forms of heart failure.